Olanzapine is a thienobenzodiazepine of formula (I):
that acts as an antagonist on receptors of dopamine D1, D2, D3, D4 and D5; of serotonine 5-HT2 and 5HT3; alpha-1-adrenergics, cholinergics and H1 histaminergics.
Olanzapine was disclosed for the first time in patent EP0454436B1, in which said thienobenzodiazepine was prepared from 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine and N-methylpiperazine in DMSO/toluene, followed by isolation of the olanzapine by addition of water and crystallisation with acetonitrile.
Patent EP0733635A1 discloses two polymorphic forms of olanzapine: Form I (metastable) and Form II (stable), Form I being that obtained in the first patent EP0454436B1.
The metastable character of Form I relates to a change of colour under ambient storage conditions.
Patents EP0733634A1, U.S. Pat. No. 5,703,232 and EP0831098A2 claim the preparation of hydrated species and of solvates from olanzapine alcohols and the use thereof for preparing Form II (stable) of olanzapine, although in U.S. Pat. No. 5,703,232 the stable form is called Form I (while in the other documents the stable form is referred to as Form II).
U.S. Pat. No. 5,637,584 claims the solvate of dichloromethane of olanzapine and a method for preparing it.
Finally, patents WO0218390A1, WO03097650A1, WO03055438A2, WO03101997 and WO2004006933A2 claim the preparation of Form I olanzapine. In patent WO0218390A1 Form I of olanzapine is prepared from the dihydrate I, from the monohydrate I or from Form II, by crystallisation in dichloromethane. In patent WO03097650A1, Form I is prepared by extraction and subsequent purification with dichloromethane of olanzapine prepared by condensation of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine and N-methylpiperazine. Said patent claims a mixed solvate of dichloromethane/water and a mixed solvate of DMSO/water. In patent WO03055438A2, Form I is prepared by successive crystallisations and decolouration in C1-C4 alcohols. In patent WO03101997, Form I is prepared by precipitation from a mixture of an organic solvent in a basic medium such as toluene and methanolic soda, seeding with Form I itself. In WO2004006933A2, Form I is prepared by crystallisation of a mixture of solvents that contain IPA. In some of the preceding patents, the Form I obtained is described as stable to colour changes.